Neurons in the ventral forebrain are critical to many neurological functions, including learning and memory, cognition, aggression, and movement. Degeneration or dysfunction of basal forebrain cholinergic neurons (BFCNs) underlies many neurological conditions, including Alzheimer's disease (AD), dementia, Korsakoff's disease, and progressive supranuclear palsy (Winkler et al., 1998). These disorders result in memory loss, impaired spatial recognition, and disturbance in language. Loss of another group of neurons in the ventral forebrain, medium spiny GABAeric (GABA) projection neurons in the striatum, underlies debilitating Huntington's disease (HD). Medium spiny GABA projection neurons are critical for coordinating movements. Patients with HD exhibit uncontrolled movements. At present, there are no effective treatment options for above diseases. Alternative therapies to protect and/or to replace the diseased neurons are urgently needed to combat these devastating diseases.
Availability of large quantity of BFCNs and medium spiny GABA projection neurons would enable the development of novel therapeutics. Many types of neural cells have been generated from self-renewing human embryonic stem cells (hESCs), cells capable of differentiating into all cell types of the human body (Zhang, 2006). Over the past decade, hESCs have been successfully differentiated to cerebral glutamatergic neurons (Li et al., 2009), midbrain dopaminergic neurons (Lee et al., 2000; Perrier et al., 2004; Yan et al., 2005), and spinal motoneurons (Li et al., 2005; Singh Roy et al., 2005). Importantly, some of these hESC-derived projection neurons have shown promise in improving behavioral deficits in animal models of diseases, including dopamine neurons in a rat model of Parkinson's disease (PD) (Roy et al., 2006; Yang et al., 2008). However, efficient differentiation of hESCs into BFCNs or medium spiny GABA projection neurons has yet to be achieved.
Needed in the art is a directed differentiation method in which primate pluripotent stem cells may be differentiated into functional BFCNs or medium spiny GABA projection neurons.